Our objective is to develop an assay to predict which patients are a high risk to develop invasive cancer at the time of biopsy-proven benign breast disease. Our approach is to quantitate cells in benign breast disease tissue which have acquired autonomous phenotypes with respect to hormones and growth factors that normally evoke an orderly pattern of growth to terminal differentiation. Such an approach will provide access to at least two key biological determinants of high cancer risk in benign breast disease; The presence of occult aggressive cancer clones and a high degree of immortality acquired by the benigh lineage. In Phase I we will determine if we can detect by in situ hybridization differences in the cellular mRNA level of EGF receptor (Erb-B), thyroxin receptor (Erb-A), insulin, IGF-1 (sommatomedin), estrogen, progesterone, glucocorticoid or prolactin receptor, HER2/neu, c-myc, c-fos and c-Ha-ras genes specifically in benign breast disease from patients at the highest cancer risk (those with invasive cancer involvement). If our approach is valid, we expect to see one or more receptor or c-onc mRNA differentially over- or under-expressed specifically in atypical proliferative hyperplasias and the differential expression selected in in situ lesions and the invasive cancers from the same patients. In phase II, we will use the validated probe(s) in a retrospective and prospective study of more than 100 patients with a range of cancer occurrence times to determine our ability to predict early occurrence of primary invasive cancer.